BIOMARKER RESEARCH IN LUNG CANCER AND ITS FUTURE IN JAPAN

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Abstract

Currently, lung cancer is regarded as a mixture of heterogeneous diseases rather than single entity of the disease in terms of prognosis and therapeutic response. The discovery of EGFR mutations in 2004 as a predictive factor for EGFR tyrosine kinase inhibitors (TKI) (gefitinib or erlotinib) really opened the door of new era of individualized approach to lung cancer.

It is noteworthy that two randomized phase 3 studies that compared gefitinib with platinum doublet therapy for patients with EGFR mutation (WJTOG 3405 and NEJ 002) were first of the trials for molecularly selected patients. They both successfully showed significantly longer PFS in the gefitinib arm. To extrapolate this finding to postoperative situation, randomized clinical trial comparing gefitinib with cisplatin plus vinorelbine as adjuvant treatment for resected stage II–III patients with EGFR mutation (IMPACT trial) is ongoing.

EML4-ALK fusion was found in 2007. It soon became evident that crizotinib, an ALK-TKI, was very active for this type of lung cancer in a phase I/II study conducted in United States and Korea. Crizotinib was quickly approved at the end of March 2012 that was within 5 years from the target discovery. In the mean time, the Japanese Lung Cancer Society published ‘Guidance for ALK gene testing in lung cancer patients’ to distribute right knowledge on diagnosis of ALK+ lung cancer.

Newly identified targets such as DDR2 mutation, FGFR1 amplification in squamous cell carcinoma, or ROS1, RET fusions in adenocarcinoma also appear to belong to the same oncologic driver as EGFR or ALK. Targeted therapies for these are being developed.

However, acquired resistance inevitably emerges after ∼10 months even in such patients. There is an urgent and unmet clinical need to develop countermeasures for acquired resistance based on biomarkers of resistance.

Despite great enthusiasm for driver gene targets, biomarkers for cytotoxic chemotherapy such as ERCC1, RRM1, TS etc. have not draw adequate attention of Japanese oncologists. Retrospective validation using samples from patients enrolled in clinical trials (LETS, WJOG4107) are being carried out. In this process, biobank infrastructure is being developed.

In this symposium, I would like to introduce the current situation of biomarker research in lung cancer and discuss future direction.

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